Homozygous UBA5 Variant Leads to Hypomyelination with Thalamic Involvement and Axonal Neuropathy

The enzyme ubiquitin-like modifier activating enzyme 5 (UBA5) plays an important role in activating ubiquitin-fold modifier 1 (UFM1) and its associated cascade. UFM1 is widely expressed and known to facilitate the post-translational modification of proteins. Variants in UBA5 and UFM1 are involved in neurodevelopmental disorders with early-onset epileptic encephalopathy as a frequently seen disease manifestation. Using whole exome sequencing, we detected a homozygous UBA5 variant (c.895C > T p. [Pro299Ser]) in a patient with severe global developmental delay and epilepsy, the latter from the age of 4 years. Magnetic resonance imaging showed hypomyelination with atrophy and T2 hyperintensity of the thalamus. Histology of the sural nerve showed axonal neuropathy with decreased myelin. Functional analyses confirmed the effect of the Pro299Ser variant on UBA5 protein function, showing 58% residual protein activity. Our findings indicate that the epilepsy currently associated with UBA5 variants may present later in life than previously thought, and that radiological signs include hypomyelination and thalamic involvement. The data also reinforce recently reported associations between UBA5 variants and peripheral neuropathy

Disease characteristics of MCT8 deficiency : an international, retrospective, multicentre cohort study

Background Disordered thyroid hormone transport, due to mutations in the SLC16A2 gene encoding monocarboxylate transporter 8 (MCT8), is characterised by intellectual and motor disability resulting from cerebral hypothyroidism and chronic peripheral thyrotoxicosis. We sought to systematically assess the phenotypic characteristics and natural history of patients with MCT8 deficiency. Methods We did an international, multicentre, cohort study, analysing retrospective data from Jan 1, 2003, to Dec 31, 2019, from patients with MCT8 deficiency followed up in 47 hospitals in 22 countries globally. The key inclusion criterion was genetically confirmed MCT8 deficiency. There were no exclusion criteria. Our primary objective was to analyse the overall survival of patients with MCT8 deficiency and document causes of death. We also compared survival between patients who did or did not attain full head control by age 1·5 years and between patients who were or were not underweight by age 1–3 years (defined as a bodyweight-for-age Z score <–2 SDs or <5th percentile according to WHO definition). Other objectives were to assess neurocognitive function and outcomes, and clinical parameters including anthropometric characteristics, biochemical markers, and neuroimaging findings. Findings Between Oct 14, 2014, and Jan 17, 2020, we enrolled 151 patients with 73 different MCT8 (SLC16A2) mutations. Median age at diagnosis was 24·0 months (IQR 12·0-60·0, range 0·0-744·0). 32 (21%) of 151 patients died; the main causes of mortality in these patients were pulmonary infection (six [19%]) and sudden death (six [19%]). Median overall survival was 35·0 years (95% CI 8·3–61·7). Individuals who did not attain head control by age 1·5 years had an increased risk of death compared with patients who did attain head control (hazard ratio [HR] 3·46, 95% CI 1·76–8·34; log-rank test p=0·0041). Patients who were underweight during age 1–3 years had an increased risk for death compared with patients who were of normal bodyweight at this age (HR 4·71, 95% CI 1·26–17·58, p=0·021). The few motor and cognitive abilities of patients did not improve with age, as evidenced by the absence of significant correlations between biological age and scores on the Gross Motor Function Measure-88 and Bayley Scales of Infant Development III. Tri-iodothyronine concentrations were above the age-specific upper limit in 96 (95%) of 101 patients and free thyroxine concentrations were below the age-specific lower limit in 94 (89%) of 106 patients. 59 (71%) of 83 patients were underweight. 25 (53%) of 47 patients had elevated systolic blood pressure above the 90th percentile, 34 (76%) of 45 patients had premature atrial contractions, and 20 (31%) of 64 had resting tachycardia. The most consistent MRI finding was a global delay in myelination, which occurred in 13 (100%) of 13 patients. Interpretation Our description of characteristics of MCT8 deficiency in a large patient cohort reveals poor survival with a high prevalence of treatable underlying risk factors, and provides knowledge that might inform clinical management and future evaluation of therapies

Urological problems after surgical treatment of scoliosis in children with myelomeningocele

We assessed urological problems and complications after scoliosis surgery in children with myelomeningocele. A total of 16 children with myelodysplasia underwent surgery for scoliosis using different surgical techniques and instrumentation systems. Mean patient age at operation as 11 years and mean postoperative followup was 3 years. All patients had urological assessment before and after surgery, including urodynamics. Urological problems after surgical correction of scoliosis developed in 6 patients (38%). Three girls had difficulty performing clean intermittent self-catheterization postoperatively because of altered body posture, a genital pressure sore and a plaster body cast, respectively. In 4 patients, including 1 girl with problems performing clean intermittent self-catheterization, lower urinary tract function was altered, leading to upper urinary tract deterioration in 1 and worsening of urinary incontinence in 3. Children with myelomeningocele have a high incidence of urological complications after surgical treatment of scoliosis. Anticipation of the problems and a thorough postoperative urological evaluation, including urodynamics, can reduce morbidity and facilitate appropriate treatmen

Reliability and discriminant validity of ataxia rating scales in early onset ataxia

Objective: To determine observer-agreement and discriminantvalidity of ataxia rating scales.Background: In children and young adults, Early Onset Ataxia(EOA) is frequently concurrent with other Movement Disorders,resulting in moderate inter-observer agreement among MovementDisorder professionals. To investigate whether subjective phenotypicassessment is replaceable by quantitative measures, we aimed todetermine inter-observer agreement and discriminant validity ofataxia rating scales.Methods: In 40 EOA patients (15 (5-34) years; mean (range)),three independent pediatric neurologists assessed quantitative ataxiarating scales (ICARS, SARA and BARS), and phenotyped the pri-mary Movement Disorder characteristic (i.e. ataxic, dystonic, myo-clonic, choreatic, tics) in each patient. We determined inter- andintra-observer agreement and specified outcomes for “primary” (i.e.unanimous ataxia identification as the primary feature by all asses-sors and/or genetic ataxic diagnosis (n526)) and “secondary” (i.e.incomplete identification of ataxia as the primary Movement Disor-der (n512)) subgroups.Results: Inter- and intra-observer agreement of ataxia ratingscales revealed high intra-class correlation coefficients (ICC: .92 -.99; for ICARS, SARA and BARS), with no significant differencesbetween “primary” and “secondary” subgroups. Total ataxia ratingscale scores revealed higher outcomes in the “primary” than the“secondary” subgroup (p&lt;.001). A multivariable regression analysisrevealed that the severity of the primary Movement Disorder charac-teristic (b .57- 1.0; p .011 - &lt;.001) predicted these higher quantita-tive outcomes. The primary movement characteristic itself did notpredict higher outcomes.Conclusions: In EOA, quantitative ataxia rating scales revealhigh inter- and intra-observer reliability, reflecting reliable applicabil-ity. However, multivariable regression analysis revealed low discrim-inant validity between ataxia and other Movement Disordercharacteristics. Despite high reliability of quantitative ataxia scores,these data implicate that preceding phenotypic characterizationremains irreplaceable

NUBPL mutations in patients with complex I deficiency and a distinct MRI pattern

Objective: To identify the mutated gene in a group of patients with an unclassified heritable white matter disorder sharing the same, distinct MRI pattern.Methods: We used MRI pattern recognition analysis to select a group of patients with a similar, characteristic MRI pattern. We performed whole-exome sequencing to identify the mutated gene. We examined patients' fibroblasts for biochemical consequences of the mutant protein.Results: We identified 6 patients from 5 unrelated families with a similar MRI pattern showing predominant abnormalities of the cerebellar cortex, deep cerebral white matter, and corpus callosum. The 4 tested patients had a respiratory chain complex. deficiency. Exome sequencing revealed mutations in NUBPL, encoding an iron-sulfur cluster assembly factor for complex., in all patients. Upon identification of the mutated gene, we analyzed the MRI of a previously published case with NUBPL mutations and found exactly the same pattern. A strongly decreased amount of NUBPL protein and fully assembled complex I was found in patients' fibroblasts. Analysis of the effect of mutated NUBPL on the assembly of the peripheral arm of complex I indicated that NUBPL is involved in assembly of iron-sulfur clusters early in the complex I assembly pathway.Conclusion: Our data show that NUBPL mutations are associated with a unique, consistent, and recognizable MRI pattern, which facilitates fast diagnosis and obviates the need for other tests, including assessment of mitochondrial complex activities in muscle or fibroblasts.</p